The aims of the research plan proposed are to evaluate the degree of sensitivity to exogenous insulin/glucagon administration in pancreatectomized man (deficient in endogenous insulin/glucagon). Euglycemic insulin clamp techniques and insulin binding studies in these patients will assess peripheral tissue insulin sensitivity and peripheral insulin receptor number and affinity; reevaluation after physiologic glucagon replacement will describe and modulation, if any, by glucagon. Kinetic studies employing the isotopes 3-3H-glucose, U-13C-glucose and U-14C-Alanine will be used to examine hepatic glucose production from glycogenolysis and/or gluconeogenesis and the effectiveness of nonoxidative glucose metabolism in these patients, basally and during glucagon replacement. Glucagon binding to hepatocytes and hepatic glycogen content will be assessed. The proposed research will provide expanded information on glucagon/insulin interrelationships and dominance in regulating glucose homeostasis in a physiologic in vivo model system (pancreatectomized man). Also, insulin/glucagon receptor studies in patients insulin/glucagon deficient may reveal a previously undescribed clinical situation of receptor "up regulation" (proliferation of specific hormone receptors in response to chronically low levels of that hormone). Lastly, with the increased utilization of a total/regional pancreatectomy for cancer therapy, these studies will address the physiologic question of whether glucagon-deficient patients need glucagon. If significant insulin sensitivity, disordered glucose homeostasis, inefficient fuel utilization and/or an acquired hepatic glycogen storage disorder can be demonstrated in pancreatectomized patients, future studies would then be directed to assess if chronic glucagon replacement would be of benefit.